PROJECT SUMMARY This fellowship is directed at training the PI as a translational scientist and preparing them to address major challenges in cancer treatment and health disparities. With the advanced training proposed here, the PI will be poised to pursue an independent position leading a research group focused on the interaction between cancer metabolism and genomic instability. Women who inherit the BRCA1 or BRCA2 mutation are at an increased risk of developing breast and ovarian cancer. These cancers are a particular challenge in minority populations where genetic testing, early diagnosis, and access to treatment are each challenges. The BRCA1 and 2 gene products are required for normal levels of repair of DNA double strand breaks (DSBs) by homologous recombination (HR), providing a rationale for the synthetic lethality strategy of blocking other forms of DSB repair to sensitize BRCA deficient cancer cells to endogenous DNA damage. Drugging DSB repair regulators such as PARP has provided proof-of-principle, but most BRCA deficient patients fail to benefit from therapy. The Kron lab has shown that the Warburg effect impacts DSB repair by driving the hexosamine biosynthetic pathway (HBP), leading to high intracellular protein O-GlcNAcylation by O-GlcNAc transferase (OGT). Importantly, BRCA deficient cells display differential sensitivity to OGT inhibition, displaying radiosensitivity and defects in DSB repair. This identifies a novel strategy for synthetic lethal targeting in BRCA deficient breast cancer. In turn, high O- GlcNAcylation can suppress the effects of PARP deficiency, suggesting that activation of OGT may be a source of intrinsic resistance to PARP inhibitors. Here, we hope to confirm that targeting O-GlcNAcylation modulates cell survival in BRCA deficient breast cancer cell lines both in vitro and in xenograft mouse models. Similarly, we will evaluate blocking O-GlcNAcylation to enhance sensitivity to PARP inhibition and drive synthetic lethality in BRCA deficient breast cancer. Finally, we will discover biomarkers that will identify patients who may benefit from treatment with OGT inhibitors. Here, we will probe gene expression signatures linked to activation of O-GlcNAcylation in BRCA deficient breast cance. Taken together these studies may provide a rationale for targeting the HBP in BRCA deficient breast cancer. Looking forward, gaining an understanding of how metabolism determines cancer risk, progression and resistance may have major impacts in reducing disparities in cancer incidence, treatment and outcomes.